The present invention relates to chimeric and humanized anti-idiotype antibodies that specifically bind carcinoembryonic antigen antibodies. The invention further relates to the uses of the chimeric and humanized anti-idiotype antibodies as clearing agents in therapeutic methods, as a vaccine, and to detect in biological fluid samples the presence of an antibody or fragment thereof that specifically binds CEA.
The use of targeting monoclonal antibodies conjugated to radionuclides or other cytotoxic agents offers the possibility of delivering such agents directly to the tumor site, thereby limiting the exposure of normal tissues to toxic agents. (Goldenberg, Semin. Nucl. Med., 19: 332 (1989)). In recent years, the potential of antibody-based therapy and its accuracy in the localization of tumor-associated antigens have been demonstrated both in the laboratory and clinical studies (see., e.g., Thorpe, TIBTECH, 11: 42 (1993); Goldenberg, Scientific American, Science & Medicine, 1: 64 (1994); Baldwin et al., U.S. Pat. Nos. 4,925,922 and 4,916,213; Young, U.S. Pat. No. 4,918,163; U.S. Pat. No. 5,204,095; Irie et al., U.S. Pat. No. 5,196,337; Hellstrom et al., U.S. Pat. Nos. 5,134,075 and 5,171,665). In general, the use of radiolabeled antibodies or antibody fragments against tumor-associated markers for localization of tumors has been more successful than for therapy, in part because antibody uptake by the tumor is generally low, ranging from only 0.01% to 0.001% of the total dose injected (Vaughan et al., Brit. J. Radiol., 60: 567 (1987)). Increasing the concentration of the radiolabel to increase the dosage to the tumor is counterproductive generally as this also increases exposure of healthy tissue to radioactivity.
Carcinoembryonic antigen (CEA) is a 180,000-Da glycoprotein expressed in most adenocarcinomas of endodermal-derived digestive-system epithelia and in some other types of cancer such as breast cancer and non-small-cell lung cancer. One of the main advantages of the CEA system is that AB1 anti-CEA have been extensively used as radioimmunodetection agents in cancer patients. One such antibody, MN-14, is a murine IgG1K monoclonal antibody (Mab) with high affinity (KD=10−9M) for human CEA. In cancer patients, 131I-MN-14 targets CEA-producing tumors effectively, and radiolabled MN-14-Fab′ can detect lesions as small as 2 cm in diameter.
Rat anti-idiotype antibody (rWI2) against an anti-carcinoembryonic antigen antibody (MN-14) has been considered as a potential idiotype vaccine, capable of eliciting an Ab3 response in immunized animals. Losman et al., Int. J. Cancer 56: 580-584 (1994). It has also been shown that WI2 can serve as an effective clearing agent improving tumor/nontumor ratios and reducing myelotoxicity, when used to remove excess radiolabeled MN-14, as shown, for example, in U.S. Pat. No. 4,624,846, the entire contents of which are incorporated herein by reference. However, its use is limited by the short biological half life of the rat Ab, due to rejection by the human host.